Action Points

Explain to interested patients that diabetes, especially in combination with atherosclerosis as indicated by peripheral arterial disease, increases risks for heart attacks and other cardiovascular events.

Caution patients that randomized controlled trial evidence does not support use of aspirin for prevention of a first cardiovascular event despite recommendations to the contrary in guidelines from the American Heart Association and other organizations.

Among patients with diabetes and asymptomatic peripheral arterial disease, aspirin did not reduce primary fatal and non-fatal cardiovascular events compared with placebo (hazard ratio 0.98, 95% confidence interval 0.76 to 1.26), reported Jill Belch, M.D., of the University of Dundee here, and colleagues online in BMJ.

Rates of death from stroke or coronary artery disease were similar between the groups in the randomized trial. The trial, which also looked at coronary disease and antioxidants, found no benefit in primary prevention for that intervention either.

This should come as little surprise, commented William R. Hiatt, M.D., of the University of Colorado in Denver, in an accompanying editorial.

Six other well-controlled trials, including the Women's Health Study and Physicians' Health Study, have shown no benefit for aspirin in primary prevention even for at-risk patients despite the well-established benefits in secondary prevention, he said.

"The mechanisms of this differential response to aspirin are not known," he wrote, "but clearly suggest that patients who respond to aspirin must have a history of clinical, symptomatic cardiovascular disease."

Dr. Hiatt was part of the FDA panel that in 2003 rejected labeling aspirin for primary prevention, citing universally negative primary prevention trials, which also failed to show a significant benefit for high-risk populations, including diabetics.

Although aspirin is cheap, universally available, and recommended in American Heart Association guidelines, the evidence just isn't there for patients without established symptomatic cardiovascular disease, he said.

AHA guidelines recommend aspirin for primary prevention in diabetes on the basis of a reduction of events in a mixed group of patients with and without cardiovascular disease in the Early Treatment of Diabetic Retinopathy Study.

"The assumption is that the positive findings of aspirin in patients with symptomatic coronary or cerebrovascular disease can be extrapolated to these high-risk populations without clinical evidence of cardiovascular disease," Dr. Hiatt said.

However, Elliott M. Antman, M.D., of Brigham and Women's Hospital, in Boston who was chair of the AHA task force that oversaw production of the guidelines, said the body of evidence for primary prevention in peripheral arterial disease is more solid, though based on sicker populations more likely to show an effect.

He said that the guidelines committee would likely look at the study to see whether an update was needed, but the level of risk in the patient population would likely be a deciding factor in whether a change is made. "It's not going to be a straight forward answer."

Meanwhile, Dr. Antman urged caution in interpreting the findings. "I'm not ready to change my practice pattern on the basis of this study."

But Dr. Hiatt said the reason for the lack of efficacy wasn't that the risk was too low to see a benefit in asymptomatic patients.

"These results support the concept that risk assessment alone cannot predict which patients will benefit from aspirin," Dr. Hiatt said, again emphasizing that the only predictor of clinical response to aspirin is a history of a major coronary or cerebral ischemic event.

The multicenter trial included 1,276 Scottish adults ages 40 and older with type 1 or 2 diabetes and peripheral arterial disease indicated by an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease.

The overall risk for their age was particularly high with an event rate of about 3% a year.

Patients were randomized to double blind treatment in a two-by-two factorial design to either one 100-mg aspirin tablet daily or placebo and either one daily antioxidant capsule -- containing vitamins E, B3, B6, and C, zinc, and selenium -- or placebo.

After an average 6.7 years of follow-up, the rate of the composite primary endpoint of death from coronary heart disease or stroke, non-fatal MI or stroke, and amputation for critical limb ischemia was similar between groups.

Aspirin did not prevent these fatal and nonfatal events compared with placebo (18.2% versus 18.3%, HR 0.98, 95% CI 0.76 to 1.26). Nor was there any benefit in this outcome with antioxidants compared with placebo (18.3% versus 18.2%, HR 1.03, 95% CI 0.79 to 1.33).

For the secondary outcome of death from coronary heart disease or stroke, aspirin was not preventive compared with placebo (6.7% versus 5.5%, HR 1.23, 95% CI 0.79 to 1.93).

All-cause mortality, though, was significantly higher with the antioxidants (P=0.006). The researchers said this was partly because of a lower-than-expected death rate in the placebo group compared with an age- and sex-matched Scottish population and partly because of a relative excess of deaths in the antioxidant group.

No significant interaction between aspirin and antioxidants emerged for either the composite primary endpoint (P=0.88) or for death from coronary heart disease or stroke (P=0.95).

No significant benefits from either treatment were seen for any subgroups by age, sex, or ankle brachial pressure index.

The study was powered to rule out any clinically important benefits, Dr. Belch's group noted.

Both treatments were well tolerated with no excess in adverse events except for more gastrointestinal side effects with antioxidants, including dyspepsia (P=0.015).

However, both Dr. Hiatt and the researchers cautioned that aspirin is not without risks.

The number needed to treat to cause an adverse event, including gastrointestinal bleeding, has been estimated at 248, Dr. Belch and colleagues said.

The study was supported by a grant from the Medical Research Council. Bayer donated the aspirin and placebo tablets; Scotia Pharmaceuticals (formerly Cardinal) provided the antioxidant capsules and matching placebo.

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